Miguel Carda - Academia.edu (original) (raw)

Papers by Miguel Carda

Pharmaceuticals

Twenty-one styryl and phenethyl aryl ureas have been synthetized and biologically evaluated as mu... more Twenty-one styryl and phenethyl aryl ureas have been synthetized and biologically evaluated as multitarget inhibitors of Vascular endothelial growth factor receptor-2 VEGFR-2 and programmed death-ligand-1 (PD-L1) proteins in order to overcome resistance phenomena offered by cancer. The antiproliferative activity of these molecules on several tumor cell lines (HT-29, MCF-7, HeLa and A549), on the endothelial cell line human microvascular endothelial cells (HMEC)-1 and on the non-tumor cell line human embryonic kidney cells (HEK)-293 has been determined. Some derivatives were evaluated for their antiangiogenic properties such as their ability to inhibit microvessel formation using HMEC-1 or their effect on VEGFR-2 in both cancer and endothelial cell lines. In addition, the immunomodulator action of a number of selected compounds was also studied on PD-L1 and c-Myc proteins. Compounds 16 and 23 (Z) and (E)-styryl p-bromophenyl urea, respectively, showed better results than sorafenib in...

Molecules

Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue 3′-aminocombretastatin A-... more Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue 3′-aminocombretastatin A-4 (AmCA-4) have shown promising antitumor activities. In this study, a range of CA-4 and AmCA-4 derivatives containing amino acid pendants have been synthesized in order to compare their biological actions with those of their parent compounds. Thus, inhibition of cell proliferation on tumor cell lines HT-29, MCF-7 and A-549, as well as on the nontumor cell line HEK-273; in vitro tubulin polymerization; mitotic cell arrest; action on the microtubule cell network and inhibition of VEGF, hTERT, and c-Myc genes have been evaluated. Some AmCA-4 derivatives bearing L-amino acids exhibited inhibition of cell proliferation at low nanomolar levels exceeding the values shown by AmCA-4. Furthermore, while CA-4 and AmCA-4 derivatives do not show significant effects on the in vitro tubulin polymerization and cell cycle arrest, some selected CA-4 and AmCA-4 derivatives are able to cause total depolyme...

Natural Product Communications

A group of 28 N-benzylidene aniline derivatives structurally related to the natural stilbene resv... more A group of 28 N-benzylidene aniline derivatives structurally related to the natural stilbene resveratrol has been prepared through condensation of anilines with the corresponding aldehydes. The ability of these imines to inhibit proliferation of two tumor cell lines (HT-29 and MCF-7) and one non-tumor cell line (HEK-293) was first determined. Subsequently, we determined the ability of some of the most cytotoxic compounds to inhibit the secretion of the VEGF-A factor in HT-29 cells and to downregulate the expression of the VEGF and hTERT genes, the latter one being involved in the activation of telomerase.

Cogent Food & Agriculture

Medicinal chemistry (Shariqah (United Arab Emirates)), Jan 20, 2018

A set of 2,5-diaryl-1,2,4-triazol-3-ones was synthesized in two steps and evaluated as regards th... more A set of 2,5-diaryl-1,2,4-triazol-3-ones was synthesized in two steps and evaluated as regards their activity in some relevant biological targets related with cancer. This study is focused to the synthesis and the biological evaluation of 2,5-diaryl-1,2,4-triazol-3-ones. In this sense, the effect of the synthetic triazolones on the proliferation of HT-29 and A549 cancer cells and on HEK non-cancer cells has been measured. In addition, the effect of triazolones on the expression of hTERT, c-Myc and PD-L1 genes and on the production of c-Myc and PD-L1 proteins have also been evaluated. A set of 2,5-diaryl-1,2,4-triazol-3-ones was synthesized in two steps. Firstly, N-(aminocarbonyl)-3-methoxybenzamide was prepared by coupling 3-methoxybenzoic acid and cyanamide followed by aqueous HCl hydrolysis. Then, the 2,5-diaryl-1,2,4-triazol-3-ones were obtained upon reaction of N-(aminocarbonyl)-3-methoxybenzamide with arylhydrazines in decaline at 170ºC. The ability of the triazolones to inhibi...

European journal of medicinal chemistry, Jan 25, 2018

Several colchicine analogues in which the N-acetyl residue has been replaced by haloacetyl, cyclo... more Several colchicine analogues in which the N-acetyl residue has been replaced by haloacetyl, cyclohexylacetyl, phenylacetyl and various aroyl moieties have been synthesized. The cytotoxic activities of the synthesized compounds have been measured on three tumor cell lines (HT-29, MCF-7 and A549) and on one non-tumor cell line (HEK-293). These compounds exhibit high antiproliferative activities at the nanomolar level, in many cases with a higher potency than colchicine itself. Some of the compounds, particularly the haloacetyl derivatives, inhibit the polymerization of tubulin in a similar manner as colchicine. As regards the cell cycle, the most active compounds are the chlorobenzoyl and bromobenzoyl derivatives, which cause cell cycle arrest at the G2/M phase when tested at 20 nM, and the bromoacetyl derivative, which arrests the cell cycle at 15 nM. In addition, these colchicine derivatives have shown fairly active downregulating the expression of the c-Myc, hTERT and VEGF genes, a...

European journal of medicinal chemistry, Jan 25, 2018

Our efforts to get therapeutically useful colchicine derivatives for the treatment of cancer have... more Our efforts to get therapeutically useful colchicine derivatives for the treatment of cancer have led us to synthetize and biologically evaluate twenty-seven N,N'-disubstituted ureas containing a colchicine moiety and an aryl fragment. The cytotoxicity of the compounds, their ability to inhibit the expression of oncogenes related to telomerase activation and to the VEGF/VEGFR-2 autocrine process, such as c-MYC, hTERT and VEGF and their capability to downregulate c-MYC and VEGFR-2 proteins and the secretion of VEGF have been measured. In these biological evaluations, we have found that the change of the acetyl group in colchicines for an N-arylurea unit causes a great improvement in anticancer properties. The most promising derivatives were compounds 6 (o-Cl) and 14 (o,o-di-F) as they were able to downregulate all the tested targets at a concentration below their IC values. Thus, the arylurea unit enhances the potential of colchicine as an anticancer agent.

European journal of medicinal chemistry, Jan 9, 2018

A series of twenty-six carbamates derived from aminocombretastatin A-4 (AmCA-4) were synthesized ... more A series of twenty-six carbamates derived from aminocombretastatin A-4 (AmCA-4) were synthesized and evaluated for their capacity to affect cell proliferation, tubulin polymerization, mitotic cell arrest, microtubule network organization, apoptosis and endothelial tubular structures in vitro. The anti-proliferative activity of the synthetic carbamates was measured on several human tumor cell lines (i.e. HT-29, MCF-7, HeLa, A-549, MDA-MB-231, HL-60) as well as on the endothelial cell line HMEC-1 and the non-tumor cell line HEK-293. The compounds showed anti-proliferative activity in the nanomolar range thereby exceeding by far the activity of combretastatin A-4 (CA-4) and, in some cases, the activity of AmCA-4. The most active compounds proved to be the carbamates bearing chloro, bromo or methoxy groups in the meta position of the phenyl ring. Moreover, all carbamates inhibited in vitro tubulin polymerization, in a similar manner to that of CA-4 and AmCA-4 by interacting with the col...

European journal of medicinal chemistry, Jan 29, 2017

The synthesis, cytotoxicity, anti-leishmanial and anti-trypanosomal activities of twelve triclosa... more The synthesis, cytotoxicity, anti-leishmanial and anti-trypanosomal activities of twelve triclosan-caffeic acid hybrids are described herein. The structure of the synthesized products was elucidated by a combination of spectrometric analyses. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis, which is the most prevalent Leishmania species in Colombia, and against Trypanosoma cruzi, which is the pathogenic species to humans. Cytotoxicity was evaluated against human U-937 macrophages. Eight compounds were active against L. (V) panamensis (18-23, 26 and 30) and eight of them against T. cruzi (19-22, 24 and 28-30) with EC50 values lower than 40 μM. Compounds 19-22, 24 and 28-30 showed higher activities than benznidazole (BNZ). Esters 19 and 21 were the most active compounds for both L. (V) panamensis and T. cruzi with 3.82 and 11.65 μM and 8.25 and 8.69 μM, respectively. Compounds 19-22, 24 and 28-30 showed higher activities than benznidazole (BNZ)....

Bioorganic & medicinal chemistry letters, Jun 1, 2017

AIDS-related cancer diseases are malignancies with low incidence on healthy people that affect mo... more AIDS-related cancer diseases are malignancies with low incidence on healthy people that affect mostly subjects already immunocompromised. The connection between HIV/AIDS and these cancers has not been established yet, but a weakened immune system is certainly the main cause. We envisaged the possibility to screen a small library of compounds synthesized in our laboratory against opportunistic tumors mainly due to HIV infection like Burkitt's Lymphoma. From cellular assays and gene expression analysis we identified two promising compounds. These derivatives have the dual action required inhibiting HIV replication in human TZM-bl cells infected with HIV-1 NL4.3 and showing cytotoxic activity on human colon HT-29 and breast adenocarcinoma MCF-7 cells. In addition, preclinical in vitro adsorption, distribution, metabolism, and excretion studies highlighted a satisfactory pharmacokinetic profile.

European journal of medicinal chemistry, Jan 23, 2016

Several colchicine analogues in which the N-acetyl residue has been replaced by aliphatic, straig... more Several colchicine analogues in which the N-acetyl residue has been replaced by aliphatic, straight-chain acyl moieties, have been synthesized. These compounds show high cytotoxic activity at the nanomolar level against the tumoral cell lines HT-29, MCF-7 and A549. Some of them exhibit activities in the picomolar range against the HT-29 line and are thus two to three orders of magnitude more cytotoxic than colchicine. In this specific cell line, the activities were found to be closely related to the length of the acyl carbon chain, an increase in the latter giving rise to an increase in the cytotoxicity with a maximum in the range of 10-12 carbon atoms, followed by a decrease in activity with still longer chains. Some of the compounds inhibit microtubule assembly and induce the formation of abnormal polymers and present in most cases better apparent affinity constants than colchicine. In addition, at IC50 concentrations the analogues block the cell cycle of A549 cells in the G2/M ph...

Chemistry - A European Journal, 2016

Chemical Biology & Drug Design, 2016

Tetrahedron Asymmetry, 2000

Archiv der Pharmazie, 2016

A group of 13 curcuminoid pyrazoles was investigated for their cytotoxicity on three tumoral cell... more A group of 13 curcuminoid pyrazoles was investigated for their cytotoxicity on three tumoral cell lines (HT-29, MCF-7, and HeLa) and one non-tumoral human cell line (HEK-293). The values obtained were compared with those of curcumin. A subset of selected derivatives was also studied for their ability to downregulate expression of the hTERT and c-Myc genes, which are both involved in telomerase activity.

Bioorganic & Medicinal Chemistry Letters, 2016

As part of our medicinal chemistry program&am... more As part of our medicinal chemistry program's ongoing search for compounds with antimalarial activity, we prepared a series of thiazole analogs and conducted a SAR study analyzing their in vitro activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. The results indicate that modifications of the N-aryl amide group linked to the thiazole ring are the most significant in terms of in vitro antimalarial activity, leading to compounds with high antimalarial potency and low cytotoxicity in HepG2 cell lines. Furthermore, the observed SAR implies that non-bulky, electron-withdrawing groups are preferred at ortho position on the phenyl ring, whereas small atoms such as H or F are preferred at para position. Finally, replacement of the phenyl ring by a pyridine affords a compound with similar potency, but with potentially better physicochemical properties which could constitute a new line of research for further studies.

Cheminform, 2000

ABSTRACT The stereoselective transformation of 2-thioamides to 2-thio-3-chloroacrylamides and the... more ABSTRACT The stereoselective transformation of 2-thioamides to 2-thio-3-chloroacrylamides and the investigation of the scope of this transformation, including extension to ester and nitrile derivatives, is described. These highly functionalised acrylamide derivatives are synthetically versatile, and their reactivity has been investigated in a wide range of transformations, including chemoselective oxidation to the racemic sulfoxide or sulfone, and enantioselective and diastereoselective oxidation to the sulfoxides. The 2-thio-3-chloroacrylamides were found to be very effective Michael acceptors in nucleophilic addition/substitution reactions, dienophiles in Diels-Alder cycloadditions, and dipolarophiles in 1,3-dipolar cycloadditions. The level of oxidation at sulfur was found to strongly influence the reactivity. This account summarises synthetic and mechanistic aspects of the research programme focussed on the synthesis and reactivity of 2-thio-3-chloroacrylamides in our research group over the past decade.

Bioorganic & Medicinal Chemistry, 2016

Chembiochem : a European journal of chemical biology, Jul 4, 2016

Resveratrol (RES) is a natural polyphenol with relevant and varied biological activity. However, ... more Resveratrol (RES) is a natural polyphenol with relevant and varied biological activity. However, its low bioavailability and rapid metabolism to its glucuronate and sulfate conjugates has opened a debate on the mechanisms underlying its bioactivity. At the same time, RES prodrugs are being developed to avoid these problems. We have synthesized a series of RES prodrugs and RES sulphate metabolites (RES-S) and evaluated their biological activity. RES glucosylated prodrugs (RES-Glc) were more cytotoxic in HT-29 and MCF-7 cells than RES itself whereas RES-S showed similar or higher cytotoxicity than RES. VEGF production was decreased by RES-Glc while RES-disulfate (RES-diS) diminished it even more than RES. Finally, RES-Glc and RES-diS inhibited hTERT gene expression to a higher extent than RES. In conclusion, resveratrol prodrugs could be promising candidates as anticancer drugs. In addition, RES-S have shown their own biological activity indicating they are not simply RES reservoirs.

Pharmaceuticals

Twenty-one styryl and phenethyl aryl ureas have been synthetized and biologically evaluated as mu... more Twenty-one styryl and phenethyl aryl ureas have been synthetized and biologically evaluated as multitarget inhibitors of Vascular endothelial growth factor receptor-2 VEGFR-2 and programmed death-ligand-1 (PD-L1) proteins in order to overcome resistance phenomena offered by cancer. The antiproliferative activity of these molecules on several tumor cell lines (HT-29, MCF-7, HeLa and A549), on the endothelial cell line human microvascular endothelial cells (HMEC)-1 and on the non-tumor cell line human embryonic kidney cells (HEK)-293 has been determined. Some derivatives were evaluated for their antiangiogenic properties such as their ability to inhibit microvessel formation using HMEC-1 or their effect on VEGFR-2 in both cancer and endothelial cell lines. In addition, the immunomodulator action of a number of selected compounds was also studied on PD-L1 and c-Myc proteins. Compounds 16 and 23 (Z) and (E)-styryl p-bromophenyl urea, respectively, showed better results than sorafenib in...

Molecules

Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue 3′-aminocombretastatin A-... more Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue 3′-aminocombretastatin A-4 (AmCA-4) have shown promising antitumor activities. In this study, a range of CA-4 and AmCA-4 derivatives containing amino acid pendants have been synthesized in order to compare their biological actions with those of their parent compounds. Thus, inhibition of cell proliferation on tumor cell lines HT-29, MCF-7 and A-549, as well as on the nontumor cell line HEK-273; in vitro tubulin polymerization; mitotic cell arrest; action on the microtubule cell network and inhibition of VEGF, hTERT, and c-Myc genes have been evaluated. Some AmCA-4 derivatives bearing L-amino acids exhibited inhibition of cell proliferation at low nanomolar levels exceeding the values shown by AmCA-4. Furthermore, while CA-4 and AmCA-4 derivatives do not show significant effects on the in vitro tubulin polymerization and cell cycle arrest, some selected CA-4 and AmCA-4 derivatives are able to cause total depolyme...

Natural Product Communications

A group of 28 N-benzylidene aniline derivatives structurally related to the natural stilbene resv... more A group of 28 N-benzylidene aniline derivatives structurally related to the natural stilbene resveratrol has been prepared through condensation of anilines with the corresponding aldehydes. The ability of these imines to inhibit proliferation of two tumor cell lines (HT-29 and MCF-7) and one non-tumor cell line (HEK-293) was first determined. Subsequently, we determined the ability of some of the most cytotoxic compounds to inhibit the secretion of the VEGF-A factor in HT-29 cells and to downregulate the expression of the VEGF and hTERT genes, the latter one being involved in the activation of telomerase.

Cogent Food & Agriculture

Medicinal chemistry (Shariqah (United Arab Emirates)), Jan 20, 2018

A set of 2,5-diaryl-1,2,4-triazol-3-ones was synthesized in two steps and evaluated as regards th... more A set of 2,5-diaryl-1,2,4-triazol-3-ones was synthesized in two steps and evaluated as regards their activity in some relevant biological targets related with cancer. This study is focused to the synthesis and the biological evaluation of 2,5-diaryl-1,2,4-triazol-3-ones. In this sense, the effect of the synthetic triazolones on the proliferation of HT-29 and A549 cancer cells and on HEK non-cancer cells has been measured. In addition, the effect of triazolones on the expression of hTERT, c-Myc and PD-L1 genes and on the production of c-Myc and PD-L1 proteins have also been evaluated. A set of 2,5-diaryl-1,2,4-triazol-3-ones was synthesized in two steps. Firstly, N-(aminocarbonyl)-3-methoxybenzamide was prepared by coupling 3-methoxybenzoic acid and cyanamide followed by aqueous HCl hydrolysis. Then, the 2,5-diaryl-1,2,4-triazol-3-ones were obtained upon reaction of N-(aminocarbonyl)-3-methoxybenzamide with arylhydrazines in decaline at 170ºC. The ability of the triazolones to inhibi...

European journal of medicinal chemistry, Jan 25, 2018

Several colchicine analogues in which the N-acetyl residue has been replaced by haloacetyl, cyclo... more Several colchicine analogues in which the N-acetyl residue has been replaced by haloacetyl, cyclohexylacetyl, phenylacetyl and various aroyl moieties have been synthesized. The cytotoxic activities of the synthesized compounds have been measured on three tumor cell lines (HT-29, MCF-7 and A549) and on one non-tumor cell line (HEK-293). These compounds exhibit high antiproliferative activities at the nanomolar level, in many cases with a higher potency than colchicine itself. Some of the compounds, particularly the haloacetyl derivatives, inhibit the polymerization of tubulin in a similar manner as colchicine. As regards the cell cycle, the most active compounds are the chlorobenzoyl and bromobenzoyl derivatives, which cause cell cycle arrest at the G2/M phase when tested at 20 nM, and the bromoacetyl derivative, which arrests the cell cycle at 15 nM. In addition, these colchicine derivatives have shown fairly active downregulating the expression of the c-Myc, hTERT and VEGF genes, a...

European journal of medicinal chemistry, Jan 25, 2018

Our efforts to get therapeutically useful colchicine derivatives for the treatment of cancer have... more Our efforts to get therapeutically useful colchicine derivatives for the treatment of cancer have led us to synthetize and biologically evaluate twenty-seven N,N'-disubstituted ureas containing a colchicine moiety and an aryl fragment. The cytotoxicity of the compounds, their ability to inhibit the expression of oncogenes related to telomerase activation and to the VEGF/VEGFR-2 autocrine process, such as c-MYC, hTERT and VEGF and their capability to downregulate c-MYC and VEGFR-2 proteins and the secretion of VEGF have been measured. In these biological evaluations, we have found that the change of the acetyl group in colchicines for an N-arylurea unit causes a great improvement in anticancer properties. The most promising derivatives were compounds 6 (o-Cl) and 14 (o,o-di-F) as they were able to downregulate all the tested targets at a concentration below their IC values. Thus, the arylurea unit enhances the potential of colchicine as an anticancer agent.

European journal of medicinal chemistry, Jan 9, 2018

A series of twenty-six carbamates derived from aminocombretastatin A-4 (AmCA-4) were synthesized ... more A series of twenty-six carbamates derived from aminocombretastatin A-4 (AmCA-4) were synthesized and evaluated for their capacity to affect cell proliferation, tubulin polymerization, mitotic cell arrest, microtubule network organization, apoptosis and endothelial tubular structures in vitro. The anti-proliferative activity of the synthetic carbamates was measured on several human tumor cell lines (i.e. HT-29, MCF-7, HeLa, A-549, MDA-MB-231, HL-60) as well as on the endothelial cell line HMEC-1 and the non-tumor cell line HEK-293. The compounds showed anti-proliferative activity in the nanomolar range thereby exceeding by far the activity of combretastatin A-4 (CA-4) and, in some cases, the activity of AmCA-4. The most active compounds proved to be the carbamates bearing chloro, bromo or methoxy groups in the meta position of the phenyl ring. Moreover, all carbamates inhibited in vitro tubulin polymerization, in a similar manner to that of CA-4 and AmCA-4 by interacting with the col...

European journal of medicinal chemistry, Jan 29, 2017

The synthesis, cytotoxicity, anti-leishmanial and anti-trypanosomal activities of twelve triclosa... more The synthesis, cytotoxicity, anti-leishmanial and anti-trypanosomal activities of twelve triclosan-caffeic acid hybrids are described herein. The structure of the synthesized products was elucidated by a combination of spectrometric analyses. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis, which is the most prevalent Leishmania species in Colombia, and against Trypanosoma cruzi, which is the pathogenic species to humans. Cytotoxicity was evaluated against human U-937 macrophages. Eight compounds were active against L. (V) panamensis (18-23, 26 and 30) and eight of them against T. cruzi (19-22, 24 and 28-30) with EC50 values lower than 40 μM. Compounds 19-22, 24 and 28-30 showed higher activities than benznidazole (BNZ). Esters 19 and 21 were the most active compounds for both L. (V) panamensis and T. cruzi with 3.82 and 11.65 μM and 8.25 and 8.69 μM, respectively. Compounds 19-22, 24 and 28-30 showed higher activities than benznidazole (BNZ)....

Bioorganic & medicinal chemistry letters, Jun 1, 2017

AIDS-related cancer diseases are malignancies with low incidence on healthy people that affect mo... more AIDS-related cancer diseases are malignancies with low incidence on healthy people that affect mostly subjects already immunocompromised. The connection between HIV/AIDS and these cancers has not been established yet, but a weakened immune system is certainly the main cause. We envisaged the possibility to screen a small library of compounds synthesized in our laboratory against opportunistic tumors mainly due to HIV infection like Burkitt's Lymphoma. From cellular assays and gene expression analysis we identified two promising compounds. These derivatives have the dual action required inhibiting HIV replication in human TZM-bl cells infected with HIV-1 NL4.3 and showing cytotoxic activity on human colon HT-29 and breast adenocarcinoma MCF-7 cells. In addition, preclinical in vitro adsorption, distribution, metabolism, and excretion studies highlighted a satisfactory pharmacokinetic profile.

European journal of medicinal chemistry, Jan 23, 2016

Several colchicine analogues in which the N-acetyl residue has been replaced by aliphatic, straig... more Several colchicine analogues in which the N-acetyl residue has been replaced by aliphatic, straight-chain acyl moieties, have been synthesized. These compounds show high cytotoxic activity at the nanomolar level against the tumoral cell lines HT-29, MCF-7 and A549. Some of them exhibit activities in the picomolar range against the HT-29 line and are thus two to three orders of magnitude more cytotoxic than colchicine. In this specific cell line, the activities were found to be closely related to the length of the acyl carbon chain, an increase in the latter giving rise to an increase in the cytotoxicity with a maximum in the range of 10-12 carbon atoms, followed by a decrease in activity with still longer chains. Some of the compounds inhibit microtubule assembly and induce the formation of abnormal polymers and present in most cases better apparent affinity constants than colchicine. In addition, at IC50 concentrations the analogues block the cell cycle of A549 cells in the G2/M ph...

Chemistry - A European Journal, 2016

Chemical Biology & Drug Design, 2016

Tetrahedron Asymmetry, 2000

Archiv der Pharmazie, 2016

A group of 13 curcuminoid pyrazoles was investigated for their cytotoxicity on three tumoral cell... more A group of 13 curcuminoid pyrazoles was investigated for their cytotoxicity on three tumoral cell lines (HT-29, MCF-7, and HeLa) and one non-tumoral human cell line (HEK-293). The values obtained were compared with those of curcumin. A subset of selected derivatives was also studied for their ability to downregulate expression of the hTERT and c-Myc genes, which are both involved in telomerase activity.

Bioorganic & Medicinal Chemistry Letters, 2016

As part of our medicinal chemistry program&am... more As part of our medicinal chemistry program's ongoing search for compounds with antimalarial activity, we prepared a series of thiazole analogs and conducted a SAR study analyzing their in vitro activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. The results indicate that modifications of the N-aryl amide group linked to the thiazole ring are the most significant in terms of in vitro antimalarial activity, leading to compounds with high antimalarial potency and low cytotoxicity in HepG2 cell lines. Furthermore, the observed SAR implies that non-bulky, electron-withdrawing groups are preferred at ortho position on the phenyl ring, whereas small atoms such as H or F are preferred at para position. Finally, replacement of the phenyl ring by a pyridine affords a compound with similar potency, but with potentially better physicochemical properties which could constitute a new line of research for further studies.

Cheminform, 2000

ABSTRACT The stereoselective transformation of 2-thioamides to 2-thio-3-chloroacrylamides and the... more ABSTRACT The stereoselective transformation of 2-thioamides to 2-thio-3-chloroacrylamides and the investigation of the scope of this transformation, including extension to ester and nitrile derivatives, is described. These highly functionalised acrylamide derivatives are synthetically versatile, and their reactivity has been investigated in a wide range of transformations, including chemoselective oxidation to the racemic sulfoxide or sulfone, and enantioselective and diastereoselective oxidation to the sulfoxides. The 2-thio-3-chloroacrylamides were found to be very effective Michael acceptors in nucleophilic addition/substitution reactions, dienophiles in Diels-Alder cycloadditions, and dipolarophiles in 1,3-dipolar cycloadditions. The level of oxidation at sulfur was found to strongly influence the reactivity. This account summarises synthetic and mechanistic aspects of the research programme focussed on the synthesis and reactivity of 2-thio-3-chloroacrylamides in our research group over the past decade.

Bioorganic & Medicinal Chemistry, 2016

Chembiochem : a European journal of chemical biology, Jul 4, 2016

Resveratrol (RES) is a natural polyphenol with relevant and varied biological activity. However, ... more Resveratrol (RES) is a natural polyphenol with relevant and varied biological activity. However, its low bioavailability and rapid metabolism to its glucuronate and sulfate conjugates has opened a debate on the mechanisms underlying its bioactivity. At the same time, RES prodrugs are being developed to avoid these problems. We have synthesized a series of RES prodrugs and RES sulphate metabolites (RES-S) and evaluated their biological activity. RES glucosylated prodrugs (RES-Glc) were more cytotoxic in HT-29 and MCF-7 cells than RES itself whereas RES-S showed similar or higher cytotoxicity than RES. VEGF production was decreased by RES-Glc while RES-disulfate (RES-diS) diminished it even more than RES. Finally, RES-Glc and RES-diS inhibited hTERT gene expression to a higher extent than RES. In conclusion, resveratrol prodrugs could be promising candidates as anticancer drugs. In addition, RES-S have shown their own biological activity indicating they are not simply RES reservoirs.